Schepens Eye Research Institute of Massachusetts Eye and Ear

Research Summary

Center/Research Area Affiliations

Biography

Dr. Chen researches the molecular mechanisms regulating the stem cell niche and axon regeneration in the adult central nervous system (CNS). Her goal is to apply this knowledge to the development of novel regenerative approaches to treat neural damage and diseases of the eye and brain. Her laboratory was the first to identify novel pathways that control optic nerve regeneration and neural stem cell growth in both the adult brain and retina, which suggests that it may be possible to reactivate dormant regenerative potential as a therapy for neurodegenerative disorders in the CNS and reversing blindness. Her laboratory subsequently achieved a landmark breakthrough by demonstrating full-length optic nerve regeneration from the eye all the way into the brain in postnatal mice through employing the technique of mouse genetic engineering. They also reported that Müller cells of adult mice possess retinal progenitor cell properties that can be activated by small molecules to generate new photoreceptors. Moreover, Dr. Chen’s laboratory has developed convenient animal models for studying the pathogenesis and drug screening strategies for glaucoma and optic nerve diseases. Aided with these tools, her group is evaluating new approaches for the treatment of glaucoma and optic neuropathy.

Honors

Her Story

Repairing a Damaged Optic Nerve

The optic nerve is a cable of nerve fibers that carry electrical impulses, containing visual information, from the eye to the brain. In adult mammals, any damage to the optic nerve caused by injury or disease tends to be permanent because the cells that form the optic nerve cannot regenerate or repair themselves. This is why glaucoma and other diseases that involve optic nerve damage, such as optic neuritis and optic nerve trauma, lead to permanent vision loss.

Similarly, nerve fibers in the brain and spinal cord share this common tragic feature of not being able to regenerate. This is most unfortunate, as a capacity for successful nerve regeneration is needed for restoration of visual function. The success of optic nerve regeneration might also open the door to future strategies of eye transplantation.

Scientists around the world are working hard to find a way to regrow the optic nerve. In addition, because of its easy access, the optic nerve has long served as a standard model for the study of spinal cord injury and regeneration in lab animals.

Steps for Optic Nerve Regeneration

Only recently has it become accepted that the failure of the optic nerve to regenerate is not a single-factor event. Successful restoration of vision after optic nerve injury can be divided into five necessary steps:

First, damaged neurons must be able to stay alive.

The surviving neurons have to be reprogrammed to turn on their growth machinery for nerve re-elongation.

The re-growing nerve fibers should be able to penetrate injury-generated scar tissue.

The regenerating fibers must overcome growth-inhibitory signals on the path they navigate.

Finally, the fibers also have to be guided back appropriately to their original target to re-form functional connections. Each of these steps presents a great challenge to our efforts to repair an injured optic nerve.

In the past, most attempts to promote optic nerve regeneration focused on only one of these steps. Some success in optic nerve regeneration, albeit very limited, was achieved: For example, Aguayo’s group [1] performed a study using growth factors, such as brain-derived nerve growth factor, to support neuron survival (targeting step one). They demonstrated a significant increase in the number of neurons surviving after injury; however, disappointingly, they found little improvement in optic nerve regeneration beyond the site of the injury.

To address step two, Monsul and Hoffman [2] in the Neuro-ophthalmology Laboratory at Johns Hopkins University injected cyclic adenosine monophosphate (cyclic AMP) into the vitreous of mice to boost the neurons’ intrinsic growth potential for nerve re-elongation. They found that cyclic AMP was effective in inducing a small number (less than 1 percent) of nerve fibers to regenerate, but only for a short distance (up to 1 mm), through the crush site.

To target steps three and four, Lehman and colleagues [3] used an enzyme called C3 to enhance neurons’ ability to penetrate glial scars and, at the same time, block nerve-growth inhibitory signals. They found that about 0.5% of nerve fibers regenerated within the injured optic nerve. Similarly, in collaboration with a group at Boston Children’s Hospital (an affiliate of Harvard Medical School), my lab [4] showed that blocking EGF-receptor signaling suppressed neurons’ responses to glial scars and to nerve-growth inhibitors. As a result, about 0.5% of severed optic nerve fibers regrew past the injury site and elongated up to 2 mm.

Recently, my laboratory achieved an important breakthrough by using combined approaches that simultaneously targeted the first three steps required for optic nerve regeneration. We demonstrated [5] that 40-70% of optic nerve fibers regenerated from the eye all the way into the brain (about 7 mm) in young mice, at ages up to two weeks after birth; this is at a time when nerve-growth inhibitors have already appeared in the mouse brain. We are now planning further studies to overcome the fourth and fifth barriers to optic nerve regeneration, and we hope that functional restoration of sight after optic nerve injury may become possible in the near future, first in mice and then in people.

With recent progress in stem cell research, neural stem cell therapy is emerging as a new approach that may be promising for restoration of sight after optic nerve injury. Attempts have focused on activating dormant stem cells, already present in the eye, to participate in the repair process in response to injury. In addition, it may be possible to harvest and transplant donor stem cells into the eyes of patients whose optic nerves have been injured, to replace the neurons that have been lost or to provide a permissive environment for nerve regrowth. Although these studies are still in their infancy, the field is progressing rapidly and may soon turn the stem cell approach into a viable therapy.

Projects

Research Interests

Functional Restoration of the Optic Nerve after Disease and Injury

We are exploring potential genetic approaches to promote regeneration of the optic nerve and restoration of function.

Military Vision Research Program

We are developing a novel stem cell and bioengineering-based regenerative approach for the treatment of retinal injury and blindness.

Novel Animal Model of Glaucoma

We are developing novel in vitro and in vivo experimental models for the study of glaucoma.

Pathological Changes of Glaucoma in Mice

The research plan proposes a collaborative effort to investigate retinal neuron and immune changes under ocular hypertension in vivo, using genetically engineered or germ-free mice as well as novel imaging technology.

Biological Inquiry into Mechanisms and Neuroprotective Strategy for Neural Trauma

We aim to elucidate the mechanisms underlying neuronal and axon damage in the brain and retina resulted from trauma and ischemia and to develop innovative neuroprotective and regenerative approaches to treat the CNS damage.

Epigenetic Regulation in Retinal Development and Diseases

This project is to define the epigenetic mechanism in retinal neuron development and degeneration for uncovering the novel insights into the contributing factors to congenital retinal dystrophy and unveiling new therapeutic targets.

Publications

Selected Publications

Dr. Chen has published more than 50 peer-reviewed articles, 15 reviews, and 5chapters. Below is a list of selected publications.